General control nonderepressible 2 (GCN2) kinase protects oligodendrocytes and white matter during branched-chain amino acid deficiency in mice

J Biol Chem. 2013 Oct 25;288(43):31250-60. doi: 10.1074/jbc.M113.498469. Epub 2013 Sep 9.


Branched-chain amino acid (BCAA) catabolism is regulated by branched-chain α-keto acid dehydrogenase, an enzyme complex that is inhibited when phosphorylated by its kinase (BDK). Loss of BDK function in mice and humans causes BCAA deficiency and epilepsy with autistic features. In response to amino acid deficiency, phosphorylation of eukaryotic initiation factor 2α (eIF2∼P) by general control nonderepressible 2 (GCN2) activates the amino acid stress response. We hypothesized that GCN2 functions to protect the brain during chronic BCAA deficiency. To test this idea, we generated mice lacking both Gcn2 and Bdk (GBDK) and examined the development of progeny. GBDK mice appeared normal at birth, but they soon stopped growing, developed severe ataxia, tremor, and anorexia, and died by postnatal day 15. BCAA levels in brain were diminished in both Bdk(-/-) and GBDK pups. Brains from Bdk(-/-) pups exhibited robust eIF2∼P and amino acid stress response induction, whereas these responses were absent in GBDK mouse brains. Instead, myelin deficiency and diminished expression of myelin basic protein were noted in GBDK brains. Genetic markers of oligodendrocytes and astrocytes were also reduced in GBDK brains in association with apoptotic cell death in white matter regions of the brain. GBDK brains further demonstrated reduced Sod2 and Cat mRNA and increased Tnfα mRNA expression. The data are consistent with the idea that loss of GCN2 during BCAA deficiency compromises glial cell defenses to oxidative and inflammatory stress. We conclude that GCN2 protects the brain from developing a lethal leukodystrophy in response to amino acid deficiencies.

Keywords: Amino Acid; Brain; Endoplasmic Reticulum Stress; Epilepsy; Gene Knock-out; Glia; Leukodystrophy; Myelin; Translation Initiation Factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Catalase / biosynthesis
  • Catalase / genetics
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism
  • Female
  • Gene Expression Regulation / genetics
  • Humans
  • Leukoencephalopathies / enzymology*
  • Leukoencephalopathies / genetics
  • Leukoencephalopathies / pathology
  • Male
  • Maple Syrup Urine Disease / enzymology*
  • Maple Syrup Urine Disease / genetics
  • Maple Syrup Urine Disease / pathology
  • Mice
  • Mice, Knockout
  • Myelin Basic Protein / biosynthesis
  • Myelin Basic Protein / genetics
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology
  • Oxidative Stress / genetics
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics


  • Eukaryotic Initiation Factor-2
  • Myelin Basic Protein
  • Tumor Necrosis Factor-alpha
  • Catalase
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Protein Kinases
  • Eif2ak4 protein, mouse
  • Protein Serine-Threonine Kinases
  • (3-methyl-2-oxobutanoate dehydrogenase (lipoamide)) kinase